Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the motor system. Autosomal-dominant familial ALS (FALS), which accounts for approximately 10% of all ALS cases, has recently been associated with missense mutations of the SOD1 gene. This gene encodes for Cu, Zn superoxide dismutase (Cu, Zn SOD), an enzyme that catalyzes the dismutation of superoxide free radicals. We and others have reported decreased SOD activity in FALS patients. In addition, we recently reported increased oxidative damage to proteins in postmortem brain tissue from SALS patients. These findings indicate that free radical-induced oxidative damage may play an important role in SALS and FALS. In this project, the possible role of oxidative damage in motor neuron degeneration will be examined. We hypothesize that FALS-associated SOD1 mutations result in decreased Cu, Zn SOD activity, that FALS and SALS arc associated with increased oxidative damage, and that free radical-induced motor neuron death may be facilitated by excitatory amino acid toxicity and impaired mitochondrial energy metabolism. To test these hypotheses, we will examine SOD activity and markers of oxidative damage in tissue (blood, cerebrospinal fluid (CSF), brain, spinal cord) from FALS and SALS patients. We will also study Cu, Zn SOD activity in bacteria that express mutant human Cu, Zn SOD. To study possible mechanisms underlying free radical-induced motor neuron degeneration, we will employ SOD1 antisense oligodeoxynucleotides and transgenic mice in in vitro spinal cord cell cultures and in vivo animal studies.